Each year approximately 100,000 people are admitted to hospitals for acute cocaine overdose, yet current treatments are merely palliative. We propose to develop butyrylcholinesterase from human plasma as a safe and effective treatment of cocaine overdose. In contrast to pharmacotherapies, which may have a benefit in treating one medical complication but can have adverse effects on another, butyrylcholinesterase is an enzyme that hydrolyzes cocaine to inactive metabolites, thereby reducing its toxicity. In preclinical studies, butyrylcholinesterase has been shown to be safe and well tolerated in doses up to 1000-fold normally present. Pretreatment with butyrylcholinesterase protected laboratory animals from the lethal cardiovascular effects of cocaine. Butyrylcholinesterase also reversed the neurotoxic effects of cocaine (hyperactivity and convulsions leading to death) when administered therapeutically after cocaine. This proposal is for the development of a commercially viable manufacturing process and for the continuation of preclinical studies of the effects of butyrylcholinesterase on cocaine metabolism. These studies will support the filing of an "Investigational New Drug" (IND) application for clinical development. The clinical program (outside the scope of this proposal) can be accomplished in less than one year and approval may be expedited via the recent designation of butyrylcholinesterase as an Orphan Drug.